Epidemiologic approaches that incorporate genetics and molecular biology have been successfully applied to a variety of common disorders. In the initial funding cycle of this proposal the investigators applied these techniques to a common sentinel birth defect--cleft lip and palate. These studies allowed identification of the association of a candidate gene, transforming growth factor alpha (TGFA), with non-syndromic cleft lip and palate. The investigators also identified the linkage localization for a syndromic form of clefting, the Van der Woude syndrome, on the long arm of chromosome 1. In the last few years there have been dramatic advances that can help extend these studies. Population-based searches have been strengthened by more robust analytic strategies and by techniques that can use very small samples volumes that may be stably acquired in the field in very large numbers. Access to international populations now allows the incorporation of diverse environmental variables into the genetic epidemiologic analysis. The range of candidate genes that can be applied in both association and linkage studies has been better defined. New awareness of novel genetic inheritance patterns that may result in non-Mendelian segregation has provided the opportunity to identify whole new classes of disorders. In this competitive renewal the investigators will extend their previous studies using linkage and association to identify genes involved in craniofacial anomalies. The studies will include an expansion of the original single Midwestern population in Iowa to multiple independent populations in the U.S. and overseas. The investigators will incorporate not only new genetics variables but also environmental variables into the analysis. In addition, unique family resources for linkage and allele loss studies will be identified from the extended population studies. The investigators will apply analytic strategies to identify multi-locus effects and nonallelic modifiers. Candidate genes for use in epidemiologic studies will be better defined using animal models and homology searches. The robustness of the DNA variants will be increased by the use of the polymerase chain reaction, new classes of more widely distributed DNA variants, and efficient sampling storage. Finally, the investigators will continue characterization of mutations for genes associated with or linked to disorders of clefting, including TGFA and non-syndromic cleft lip and palate, positional cloning efforts for the Van der Woude syndrome gene, and studies of newly established candidate genes or linkages. The investigators state that the final product of these efforts will be a better defined group of genes that play a role in craniofacial development and an improved understanding of the effects of environmental influences on developmental biology. They further state that these studies will lead to enhanced understanding of human embryogenesis, a better definition of inheritance patterns for genetic counseling, and insights into approaches that may allow manipulation of environmental variables in a way that can decrease that incidence of common birth defects.